Treating neoplasms with neurotoxin

Abstract

The present invention provides a method of treating a neoplasm using a neurotoxin, preferably botulinum toxin. Neurotoxin administered around a neoplasm acts to decrease the contractile forces of the muscles surrounding a neoplasm which normally squeeze neoplastic cells through efferent channels leaving the neoplasm to distant sites. The present invention also provides a method of administering botulinum toxin at sites distant from the neoplasm, thereby enhancing cellular and humoral immunologic functions, which further contribute to neoplastic cell death. Following administration of botulinum toxin around or distant to a neoplasm as described herein, local, regional, and distant spread of neoplastic cells is reduced or eliminated. Immunomodulation with botulinum toxin is also valuable in treating other diseases that may or may not be associated with cancers, such as viral-induced growths, viral conditions, fungal disease, chronic wounds, graft versus host disease, autoimmune disease, and HIV.

Description

INCORPORATION BY REFERENCE[0001]This application is a continuation-in-part application of U.S. patent application Ser. No. 11 / 577,838 filed Apr. 24, 2007, which is the national stage of International Application No. PCT / US05 / 33982, filed Sep. 23, 2005, which claims the benefit of priority of U.S. provisional application Ser. No. 60 / 612,443, filed Sep. 23, 2004, and this application claims the benefit of priority of U.S. provisional application Ser. No. 61 / 118,036, filed Nov. 26, 2008.[0002]The foregoing applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference...

AI Technical Summary

Benefits of technology

[0047]The present invention provides a method of treating a cancer using a neurotoxin, preferably botulinum toxin, either alone or in combination with an anti-cancer drug or therapy. Neurotaoxin administered to the non-neoplastic tissue around a neoplasm (i.e., avoiding the neoplasm) acts to decrease the squeezing effect of contractile cells on the spread of neoplastic cells through tissue and through tubules draining the neoplasm. In certain embodiments, the methods described herein paralyze the lymphatic muscle that squeezes neoplastic cells and lymph through the circulation. In certain embodiments, the methods described herein also positively modulate the immune system to enhance cellular or humoral mechanisms against the neoplasm. Following administration of botulinum toxin around a neoplasm, regional and distant spread is reduced or eliminated.

[0048]It is an object of the invention to administered botulinum neurotoxin in such a way that a therapeutically effective amount of the botulinum neurotoxin surrounds but does not penetrate a neoplasm. It is another object of the invention to administer botulinum toxin to inhibit growth, invasion or spread of neoplasic cells. The methods described herein are easily adapted to, for example, cancer therapy at the time a cancer is initially diagnosed and could significantly improve the outcome of a patient diagnosed with cancer by reducing local, regional or distant spread of the cancerous cells. In certain embodiments, the methods described herein may be used for patients undergoing either surgery, radiation therapy, chemotherapy or other forms of treatment for the diagnosed cancer. It may also be used as a sole modality of therapy.

[0059]In one embodiment, the neurotoxin denervates muscle tissue surrounding the neoplasm and / or minimizes and / or stops lymphatic flow in the region outside of the neoplasm.

[0060]In another embodiment, the botulinum toxin weakens contraction of muscle fibers in the non-neoplastic tissue around the neoplasm.

Problems solved by technology

Cancer metastasis is comprised of multiple complex, interacting, and interdependent steps, each of which is rate-limiting, since a failure to complete any of the steps prevents the tumor cell from producing a metastasis.

Because these drugs damage DNA, they can cause long-term damage to the bone marrow.

In a few rare cases, this can eventually lead to acute leukemia.

A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses.

Mitoxantrone is an anti-tumor antibiotic that is similar to doxorubicin in many ways, including the potential for damaging the heart.

This drug also acts as a topoisomerase II inhibitor, and can lead to treatment-related leukemia.

Treatment with topoisomerase II inhibitors increases the risk of a second cancer—acute myelogenous leukemia.

These drugs work during the M phase of the cell cycle, but can damage cells in all phases.

These drugs are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect.

Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories.

These cancer treatment hormones do not work in the same ways as standard chemotherapy drugs, but rather by preventing the cancer cell from using the hormone it needs to grow, or by preventing the body from making the hormones.

Third, the botulinum toxin appears to reduce a SNAP disulfide bond resulting in disruption in zinc (Zn++) endopeptidase activity, which selectively cleaves proteins important for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic surface of the plasma membrane, and fusion of the vesicles with the plasma membrane.

Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.

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